New treatments in Alzheimer disease and the continued need for placebo-controlled trials.
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Alzheimer Disease↗
Biomedical subjects
M R Farlow
Publications and source records attributed to M R Farlow.
Cerebrospinal fluid homovanillic acid levels in rapid-onset dystonia-parkinsonism.
Rapid-onset dystonia-parkinsonism (RDP) is characterized by sudden onset over hours to days of dystonia, dysphagia, dysarthria, and parkinsonism. RDP has been reported by our group in two apparently unrelated families. We now report analysis of cerebrospinal fluid metabolites of dopamine, norepinephrine, and serotonin for mild and severely affected individuals, known asymptomatic gene carriers, and at-risk individuals from both families with RDP. Levels of the dopamine metabolite homovanillic acid (HVA) were decreased in severely affected patients and in some asymptomatic gene carriers. HVA levels increased with treatment in some affected individuals, but this increase did not predict clinical response to carbidopa/levodopa. We suggest that a low HVA level is a biological marker with modest association to the diagnosis of RDP.
Adult↗
A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group.
The efficacy and safety of donepezil as a treatment for patients with mild to moderate Alzheimer's disease (AD) was investigated in a multicenter, double-blind study. Patients were randomly assigned to treatment with placebo (n = 162), 5 mg/d donepezil (n = 154), or 10 mg/d donepezil (n = 157) for 24 weeks followed by a 6-week, single-blind placebo washout. The primary efficacy measures were the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS-cog) and the Clinician's Interview Based Assessment of Change-Plus (CIBIC plus), with the Mini-Mental State Examination (MMSE), Clinical Dementia Rating Scale-Sum of the Boxes (CDR-SB), and patient rated Quality of Life (QoL) used as secondary measures. Cognitive function, as measured by the ADAS-cog, was significantly improved in the 5- and 10-mg/d donepezil groups as compared with the placebo group at weeks 12, 18, and 24. Clinician's global ratings on the CIBIC plus also improved in both the 5- and 10-mg/d donepezil groups relative to placebo. At the end of the 6-week placebo washout phase, ADAS-cog scores and CIBIC plus ratings were not significantly different for the three groups. Significant treatment benefits were also observed consistently in both the 5- and 10-mg/d groups on the MMSE and the CDR-SB, but there was no consistent effect on the patient-rated QoL. Cholinergic side effects (primarily diarrhea, nausea, and vomiting) were reported more often in the 10-mg/d group than either the 5-mg/d or placebo groups. Side effects were transient and generally mild in severity. These data indicate that donepezil is a well-tolerated drug that improves cognition and global function in patients with mild to moderate AD.
Aged↗
Cognitive decline and education in mild dementia.
Recent studies suggested that education may modify the clinical expression of dementia and Alzheimer's disease through its association with a brain reserve capacity. We studied whether education would be related to degree of cognitive decline in mild dementia. Equations to estimate premorbid cognitive ability were derived from a representative normative sample of 83 community-dwelling African Americans using age, education, and gender as independent variables and Word List Learning (WLL) and Animal Fluency (AF) scores from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological test battery as dependent variables. These equations were applied to a second sample of 131 African Americans (22 with dementia, 109 healthy) who completed CERAD test batteries as part of an epidemiologic study of dementia in the community. Differences between obtained and estimated premorbid WLL and AF test scores were calculated and then analyzed in a 2 (Education) x 2 (Diagnosis) ANOVA. A significant interaction association between Education and Diagnosis on WLL scores and a borderline significant interaction on AF scores showed that the high-education demented group had a greater cognitive decline from estimated premorbid levels than the low-education demented group. Thus, at comparable levels of clinical dementia severity, greater cognitive decline occurred in highly educated patients than in low-educated patients.
Aged↗
Treatment outcome of tacrine therapy depends on apolipoprotein genotype and gender of the subjects with Alzheimer's disease.
We studied the effects of apolipoprotein E (APOE) genotype and gender on clinical response to tacrine in patients with mild to moderate Alzheimer's disease (AD). We analyzed data from a previously reported 30-week, double-blind, placebo-controlled trial of tacrine, in which APOE genotypes were determined from previously collected plasma samples. Patients were assigned to placebo or tacrine with daily dosages of 80, 120, or 160 mg/day. The outcome measures were Alzheimer's Disease Assessment Scale-Cognitive Component, Clinician Interview Based Impression, Mini-Mental State Examination, and the Caregiver-rated Clinical Global Impression of Change. An intent-to-treat (ITT) analysis of patients with available genotypes (n = 528) did not reveal response differences by genotype, although the effect size was twice as large in the epsilon2-3 as the epsilon4 group (-2.62 versus -1.25). The association of treatment effect with APOE genotype varied significantly according to gender (p < 0.002 for ITT; p < 0.05 for evaluables). The treatment effect was larger in the epsilon2-3 compared with epsilon4 women (ITT, 4.24 points, p = 0.03; evaluable, 7.20 points, p = 0.01). In contrast, treatment effect size was not different between epsilon2-3 and epsilon4 of men with AD. APOE genotype and gender may predict response to tacrine in patients with AD.
Aged↗
Pharmacologic treatment of cognition in Alzheimer's dementia.
Much of the treatment research and development for Alzheimer's disease (AD) in recent years has been based on the cholinergic hypothesis. Cholinesterase inhibition has been shown to improve the symptoms of mild to moderate AD. Two cholinesterase inhibitors (CIs) are now available and two more may be available shortly. Free radical inhibitors, estrogen, and anti-inflammatory drugs may also delay the onset and slow progression of AD. Combination therapies employing CIs and these other drugs may prove successful in the future.
Alzheimer Disease↗
Rapid-onset dystonia-parkinsonism: a report of clinical, biochemical, and genetic studies in two families.
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Adolescent↗
Recent advances in the treatment of Alzheimer's.
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Alzheimer Disease↗
Effects of cholinesterase inhibitors on the secretion of beta-amyloid precursor protein in cell cultures.
One of the main characteristics of Alzheimer's disease (AD) is the cerebrovascular deposition of the amyloid beta-peptide (A beta), which is derived from a larger beta-amyloid precursor protein (beta APP). The majority of beta APP is processed by either a secretory of lysosomal/endosomal pathway. Carboxyl-truncated soluble derivatives of beta APP (sAPP) are generated by the proteolytic processing of full-length beta APP by either alpha- or beta-secretase enzyme. Our objective is to determine whether the processing of beta APP can be regulated by cholinesterase inhibitors, some of which were shown to produce a moderate improvement in memory and cognitive functions in patients with Alzheimer's disease. Here we have analyzed the levels of sAPP derivatives in cultured cells treated with different drugs by immunoblotting samples of conditioned media. The immunoreactive protein bands were developed by probing with the monoclonal antibody 22C11. Treating neuroblastoma, pheochromocytoma and fibroblast cells with high dose of either 3,4-diaminopyridine, metrifonate, or physostigmine did not inhibit the secretion of sAPP. Treating glioblastoma with either 3,4-diaminopyridine or metrifonate showed an increase in secretion of sAPP. However, treatment of cells with tacrine reduced release of sAPP in conditioned media of cell lines studied. The difference in action of metrifonate, physostigmine, and tacrine on beta APP is independent of their anticholinesterase activities. Our results suggests that noncatalytic functions of cholinesterase inhibitors can be utilized to alter the metabolism of beta APP, which might in turn affect the process of deposition of A beta, a key component of the cerebrovascular amyloid detected in AD.
4-Aminopyridine↗
Potential role for estrogen replacement in the treatment of Alzheimer's dementia.
In light of evidence that estrogen replacement therapy (ERT) might affect cholinergic function, we examined possible effects of ERT on clinical and cognitive responses to the cholinesterase inhibitor tacrine in women with Alzheimer's disease (AD). In a previously reported 30-week, randomized, double-blind, placebo-controlled, multicenter clinical trial, 14.5% of 318 women with evaluable data had been receiving ERT prior to randomization. Patients were randomly assigned to receive placebo or one of three ascending dosages of tacrine (maximum dosages of 80 mg/day, 120 mg/day, or 160 mg/day). Women completing the trial receiving ERT and tacrine improved more than women not receiving ERT who were randomized to tacrine or to placebo as assessed by cognitive (p <0.01), clinical (p = 0.02), caregiver (p = 0.006), and mental status (p = 0.07) ratings. Using an intent-to-treat analysis, they improved significantly on cognitive ratings (p = 0.01). These results provide evidence that prior and continuing ERT may enhance response to tacrine in women with AD. Randomized trials are needed.
Alzheimer Disease↗
Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments.
Neurofibrillary lesions made of hyperphosphorylated microtubule-associated protein tau constitute not only one of the defining neuropathological features of Alzheimer disease but also are present in a number of other neurodegenerative diseases with dementia. Here we describe a novel autosomal dominant disease named familial "multiple system tauopathy with presenile dementia," which is characterized by abundant fibrillary deposits of tau protein in both neurons and glial cells. There are no detectable deposits of beta-amyloid. The tau deposits are in the form of twisted filaments that differ in diameter and periodicity from the paired helical filaments of Alzheimer disease. They are stained by both phosphorylation-independent and -dependent anti-tau antibodies. Moreover, tau immunoreactivity coexists with heparan sulfate in affected nerve and glial cells. Tau protein extracted from filaments of familial multiple system tauopathy with presenile dementia shows a minor 72-kDa band and two major bands of 64 and 68 kDa that contain mainly hyperphosphorylated four-repeat tau isoforms of 383 and 412 amino acids.
Aged↗
Hereditary neuralgic amyotrophy: evidence for genetic homogeneity and mapping to chromosome 17q25.
Hereditary neuralgic amyotrophy (HNA) is a rare autosomal dominant disorder on chromosome 17q, associated with recurrent, episodic, painful brachial plexus neuropathy. Dysmorphic features, including hypotelorism, long nasal bridge and facial asymmetry, are frequently associated with HNA. To assess genetic homogeneity, determine the cytogenetic location, and identify flanking markers for the HNA locus, six pedigrees were studied with multiple DNA markers from distal chromosome 17q. The results in all pedigrees supported linkage of the HNA locus to chromosome 17. A maximum combined lod score (Z = 10.94, theta = 0.05) was obtained with marker D17S939 and the maximum multipoint lod score was 22.768 in the interval defined by D17S802-D17S939. An analysis of crossovers placed the HNA locus within an approximate 4.0-cM interval flanked by D17S1603 and D17S802. Analysis of DNA from a human/mouse somatic cell hybrid with linked markers suggests that band 17q25 harbors the HNA locus. These results support genetic homogeneity within HNA and define a specific interval and a precise cytogenetic location in chromosome 17q25 for this disorder.
Brachial Plexus↗
The effect of tacrine and leupeptin on the secretion of the beta-amyloid precursor protein in HeLa cells.
The senile plaque in Alzheimer's disease (AD) consists mainly of the amyloid beta-peptide (A beta) derived from a larger beta-amyloid precursor protein (betaAPP). The majority of betaAPP is processed by either a secretory or lysosomal/endosomal pathway. Soluble derivatives of betaAPP (sAPP) and A beta generated by the proteolytic processing of full-length betaAPP are normally secreted into the conditioned medium of cultured cells. Tacrine, a centrally active potent cholinesterase inhibitor that has been shown to improve cognitive functions in some patients with AD, inhibits the secretion of sAPP. Here we have investigated whether leupeptin, a lysosomal protease inhibitor, could influence this effect of tacrine. We analyzed levels of betaAPP derivatives in cultured HeLa cells by immunoblotting cell lysates and conditioned media using the monoclonal antibody 22C11. Levels of sAPP normally present in conditioned media were severely reduced by treating cells with tacrine. The treatment of cells with tacrine resulted in a small decrease in the intracellular levels of betaAPP. The effect of treating the cells with tacrine did not depend upon the growing state of the cells as a similar effect was observed when the drug was added either during initial plating of the cells or after the attachment of the cells. The effect of tacrine was not affected by preincubating the cells with low serum in the culture medium. The treatment of cells with tacrine plus leupeptin reduced the secretion of sAPP in the medium to the same degree as did the treatment with tacrine alone, suggesting that the tacrine-mediated inhibition of sAPP release may not involve leupeptin-sensitive proteolytic pathways. The results suggest that the inhibitory effect of tacrine on sAPP secretion is not due to the proteolytic cleavage of the holoprotein in the medium.
Alzheimer Disease↗
Familial multiple-system tauopathy with presenile dementia is localized to chromosome 17.
An autosomal dominant presenile dementia affecting 39 individuals in a seven-generation, 383-member pedigree has been studied at Indiana University. In the affected members of this family, clinical symptoms occurred early in life, with an average age at onset of 48.8 years. The presenting clinical features include disequilibrium, neck stiffness, dysphagia, and memory loss. As the disease progresses, further cognitive decline, superior-gaze palsy, and dystaxia also are observed. The average duration from onset of symptoms to death is approximately 10 years. Neuropathologic studies of nine affected individuals showed neuronal loss in several areas of the CNS, as well as argentophilic tau-immunopositive inclusions in neurons and in oligodendroglia. A limited genomic screen by use of DNA samples from 28 family members localized the gene for this disorder to a 3-cM region on chromosome 17, between the markers THRA1 and D17S791. The gene for tau also was analyzed, through samples from the family.
Adult↗
Rapid-onset dystonia-parkinsonism in a second family.
Rapid-onset dystonia-parkinsonism (RDP), first described in a large Midwestern family, is now reported in a second, apparently unrelated, family in which four individuals have this same syndrome. All four developed sudden onset of dysarthria, dysphagia, severe dystonic spasms, bradykinesia, and postural instability over less than 1 hour to a few days. Three of the four had stable limb dystonia for several years preceding the onset of combined dystonia-parkinsonism. Treatment with levodopa/carbidopa provided little benefit. We propose diagnostic criteria for RDP and further define the spectrum of this unusual disease.
Adolescent↗
Alzheimer's disease: clinical implications of the apolipoprotein E genotype.
Inheritance of the apolipoprotein E (APOE = gene; apoE = protein) epsilon 4 gene is associated with a higher risk for development of Alzheimer's disease (AD) and for occurrence of this illness at a younger age. APOE gene dose and genotype interact with gender, ethnicity, and age to influence the probability of developing AD, as well as the rate of disease progression. The sensitivity and specificity of APOE genotyping, however, and the longer-term implications of the epsilon 4 allele as a susceptibility factor for AD, are not yet adequately understood to recommend the use of APOE genotyping in genetic counseling of asymptomatic family members of AD patients. Insufficient evidence also exists at this time to recommend APOE genotyping as an adjuvant for the differential diagnosis of dementia or as a possible predictor for response to drug therapy. These potential future clinical indications for apoE genotyping are under active investigation.
Age of Onset↗
Optimal management of behavioural disorders associated with dementia.
Behavioural disorders occur with great frequency in patients with dementia. They are the major reason for admission of these patients to nursing homes. However, there have been few controlled trials of many of the commonly used drugs to guide therapy. To treat these conditions successfully, an adequate description of target symptoms of the behaviours to be corrected and a thorough investigation to identify precipitating causes are essential. Behavioural problems in dementia patients may results from physical illnesses, adverse drug effects, environmental changes, psychiatric syndromes (i.e. depression, delirium or psychosis) or the dementing illness itself. Therapeutic strategies should address the underlying cause whenever possible. Although pharmacological therapies are commonly employed, their efficacy is often modest and adverse effects can be quite significant. Ongoing reassessments are essential to maximise symptomatic benefits and minimise adverse effects. Several trials with different drugs are often necessary before an effective therapy is found. Anticholinergic adverse effects, which occur commonly with many antipsychotic and antidepressant medications, may worsen the cognitive and memory deficits that form the primary symptoms of dementia in these patients. This article summarises the use of the various psychoactive medications that target common behavioural disturbances, including agitation, psychosis, depression and sleep disturbances, in dementia patients. General guidelines regarding dosage, potential adverse effects and duration of therapy are discussed.
Aggression↗
Hereditary spastic paraplegia: LOD-score considerations for confirmation of linkage in a heterogeneous trait.
Hereditary spastic paraplegia (HSP) is a degenerative disorder of the motor system, defined by progressive weakness and spasticity of the lower limbs. HSP may be inherited as an autosomal dominant (AD), autosomal recessive, or an X-linked trait. AD HSP is genetically heterogeneous, and three loci have been identified so far: SPG3 maps to chromosome 14q, SPG4 to 2p, and SPG4a to 15q. We have undertaken linkage analysis with 21 uncomplicated AD families to the three AD HSP loci. We report significant linkage for three of our families to the SPG4 locus and exclude several families by multipoint linkage. We used linkage information from several different research teams to evaluate the statistical probability of linkage to the SPG4 locus for uncomplicated AD HSP families and established the critical LOD-score value necessary for confirmation of linkage to the SPG4 locus from Bayesian statistics. In addition, we calculated the empirical P-values for the LOD scores obtained with all families with computer simulation methods. Power to detect significant linkage, as well as type I error probabilities, were evaluated. This combined analytical approach permitted conclusive linkage analyses on small to medium-size families, under the restrictions of genetic heterogeneity.
Chromosomes, Human, Pair 14↗